There are currently no treatments available that facilitate LTP and there are no clinical trials of such products. LTP failure is implicated in Angelman Syndrome. Without being bound by any particular theory, it is believed that Angelman syndrome (AS) is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements especially hand-flapping, frequent laughter or smiling, and usually a happy demeanor. Some in the art believe that AS is a classic example of genetic imprinting in that it is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15. The related syndrome, Prader-Willi syndrome, is believed caused by a similar loss of paternally-inherited genes.
CN2097 and related compounds are presented in U.S. Provisional Patent Application Ser. No. 61/179,055, entitled “Cyclic-GluR6 Analogs, Methods of Treatment and Use” (Spaller et al.) the teachings of which are incorporated herein by reference in their entirety. CN 2097 is a peptidomimetic drug that selectively targets the PDZ binding domain of the PSD-95, a scaffolding protein involved in the development and regulation of neuronal synapses CN 2097 has demonstrated specificity for the NMDA receptor 2B (NR2B) subunit. The association of PSD-95 with NMDA receptors is an element in the propagation of the synaptic changes of LTP and long-term depression (LTD) that induce learning and memory. PSD-95 is a member of the MAGUK-family of PDZ domain-containing proteins. Its basic structure includes three PDZ domains, an SH3 domain, and a guanylate kinase-like domain (GK).
Angelman syndrome is a result of loss-of-function mutations or deletions in the maternally inherited allele of UBE3A. Mice that are deficient in maternal Ube3a also show genetically reversible deficits in learning and the induction of hippocampal long-term potentiation (LTP)1-3, a form of synaptic plasticity. Angelman syndrome (AS) is caused by disruptions in function due to mutations and/or deletions in the maternally inherited allele of an E3 ubiquitin ligase, UBE3A, a gene that has also been implicated in the broader spectrum of Autism patients. A mouse model for AS carries the maternally inherited Ube3a-null mutation and shows profound impairments in hippocampal synaptic plasticity as seen in FIG. 8. It has been reported that UBE3A is also required for experience dependent maturation in the visual cortex. In particular, AS mice show deficits in long-term potentiation (LTP) and long-term depression (LTD), which are the cellular substrates of learning and memory. These forms of synaptic plasticity are highly regulated by activity-dependent changes in the ratio of NMDA subunits, specifically NR2A and NR2B subunits. NMDA receptors gate the influx of calcium ions across the post-synaptic membrane. Depending on the characteristics of the calcium influx generated in response to pre-synaptic activity, either LTP or LTD can be induced. This calcium influx activates calcium-dependent enzymes such as CaMKII, which has been strongly implicated in Angelman syndrome, and triggers its autophosphorylation at Thr286. This autophosphorylation is very important as it allows the enzyme to remain active once the calcium levels return to normal. This pathway requires an interplay between the NMDA receptor, CaMKII and a post-synaptic scaffolding protein (PSD-95 in particular), which brings these biochemical elements into proximity. Thr286 autophosphorylation is instrumental in promoting the association of CaMKII with the PSD by directly binding to the NMDA receptor. Interestingly, there is also a secondary inhibitory autophosphorylation at Thr305/306 that has been suggested to regulate the association of CaMKII to the PSD. Interplay between these states can govern the availability of CaMKII to regulate synaptic plasticity in response to calcium influx during learning and memory activity. The clinical features of AS have been linked to the misregulation of alpha CaMKII function. The role of CaMKII in synaptic plasticity and AS has been investigated at the synapses of the Schaffer-collateral-CA1 pyramidal cells in the adult hippocampus.
Noted is the Szeto-Schiller (SS) peptide (Dmt-D-Arg-Phe-Lys-NH2; where Dmt=2′,6′-dimethyltyrosine). This represents an approach with targeted intracellular delivery, including to the inner mitochondrial membrane. The structural motif of the SS peptide centers on alternating aromatic residues and basic amino acids (aromatic-cationic peptides). They are small, easy to synthesize, readily soluble in water, and resistant to peptidase degradation. The presence of a D-amino acid in either the first or second position renders them resistant to aminopeptidase activity, and amidation of the C-terminus reduces hydrolysis from the C-terminus. Despite carrying 3+ net charge at physiological pH, these peptides have been reported to readily penetrate cell membranes of a variety of cell types. This is further set forth in Zhao K, Luo G, Zhao G M, Schiller P W, Szeto H H. Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther. 2003; 304:425-432. PubMed DOI: 10.1124/jpet.102.040147
Noted are neurotrophins. Neurotrophins are a family of neurotrophic factors involved in the development, maintenance, and repair of the nervous system. The neurotrophin family consists of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5. The neurotrophins are believed to bind to and activate Trk family proteins, the receptor tyrosine kinases (RTK), to exert their effects. NGF binds to TrkA, BDNF and NT-4/5 bind to TrkB, and NT-3 binds to TrkC. The neurotrophins BDNF and NGF and their high-affinity receptor Trk receptor are reported as widely expressed in neurons throughout the central nervous system. Binding of neurotrophins to Trk receptor is reported to result in phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor and subsequent recruitment and activation of various signaling adaptor proteins, including Shc, Gab1, and shp2. 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